According to the American Society of Anesthesiologist's Statement on Pain Relief During Labor, “Labor results in severe pain for many women. There is no circumstance where it is considered acceptable for a person to experience untreated severe pain, amenable to safe intervention, while under a physician's care. In the absence of a medical contraindication, maternal request is a sufficient medical indication for pain relief during labor. Pain management should be provided whenever medically indicated.” While many non- and minimally-invasive, non-pharmacologic pain therapies have been promoted, including prepared childbirth, imagery, hypnosis, transcutaneous electrical nerve stimulation (TENS), intracutaneous sterile water injection, chiropractic, hydrotherapy, acupuncture, etc, many women opt for medications or methods to numb the nerves sensing labor pain. However the vast majority of patients prefer to remain awake and able to participate in the birth of their child. Any pain management technique must take into account both the safety of the mother, and of the fetus. Agents that cross into the maternal brain for effect (e.g. sedatives and most i.v. analgesics) can similarly cross the placental barrier and reach the fetus.
The first stage of labor is characterized by brief (1-2 minute) intervals of severe pain, followed by moments of relative comfort. Current pharmacologic options for labor analgesia during this stage include i.v. opioids, paracervical nerve blocks, inhalational analgesia (much more common outside the United States), and neuraxial anesthesia (spinal or epidural). There are advantages and disadvantages to each.
An array of opioids has been studied in labor, but there is little scientific basis to suggest an advantage of one drug over another in the obstetric setting. Worldwide, intravenous opioids are the most common labor analgesic. Opioids share side effects including nausea/vomiting, pruritus, sedation, changes in heart rate (both maternal and fetal) and, of most concern, respiratory depression. Moreover, due to their lipophilicity, all opioids readily cross the placenta, entering fetal circulation. Thus, i.v. opioids have the potential for adverse neonatal effects (e.g., decreased beat-to-beat variability in the fetal heart rate pre-delivery, and neonatal respiratory depression). Further, the efficacy of opioids is limited due to the character of labor pain; for example, doses of i.v. opioids sufficient to provide analgesia during contractions cause unacceptable side effects between contractions.
Paracervical blocks require the administration of local anesthetics into the cervix where the sensory nerves from the uterus exit. While this provides excellent analgesia for the first stage of labor, the proximity of the injection site to the uterine arteries causes an unacceptable frequency of fetal bradycardia. For this reason, paracervical blocks rarely are used in the United States.
Pudendal blocks provide analgesia for the second stage of labor and are relatively safe. The most difficult issue is timing, in that the pain relief is only of the sacral nerves, and is therefore not useful until the fetal head is low. However, at that time, it is often difficult to access the anatomic location in the pelvis for appropriate placement of the block.
Modern inhalation analgesia consists almost exclusively of nitrous oxide. Though rarely used in the United States, various concentrations of nitrous oxide in oxygen are routinely used to relieve labor pain elsewhere, either alone or as an adjunct to other analgesic techniques. In most cases the patient self-administers a set concentration (30-70%) of nitrous oxide as she senses the onset of a contraction. Limitations include hypoxia, pollution of the local environment, occupational exposure, and the timing of nitrous oxide inhalation relative to the onset of contraction-induced pain.
Epidural analgesia involves the placement of local anesthetic and/or opioids into the epidural space. While an epidural usually provides superb analgesia, its placement is objectionable to some patients, contraindicated in others, and may be unavailable at many small hospitals. Usually a catheter is left in the space for continuous infusion of analgesics. This method of analgesia is more effective than i.v. opioids and results in less maternal and neonatal depression because of lower blood opioid levels. Furthermore, should the patient require a cesarean delivery, the epidural catheter can be used for surgical anesthesia. There are, however, risks associated with the placement of an epidural including headache, bleeding, infection, and nerve damage. Furthermore, epidural analgesia is contraindicated in some conditions (hemorrhage, coagulopathy), not offered at many hospitals, particularly smaller facilities, and is rare in many parts of the world.
While neuraxial analgesia provides superior pain relief, an effective alternative is necessary for those patients in whom neuraxial analgesia is either contraindicated or objectionable. Currently regimens utilizing morphine or meperidine provide more sedation than actual analgesia (Olofsson C et al., “Lack of analgesic effect of systemically administered morphine or pethidine on labour pain,” Br. J. Obstet. Gynaecol., 968-72 (1996)), and the same may be true for remifentanil, particularly as labor progresses and pain increases. However, despite pain scores that remain in the moderate range (6-8 cm), patients consistently report improved satisfaction with remifentanil versus meperidine.
Remifentanil hydrochloride is an ultra-short acting, phenylpiperidine μ-specific opioid receptor agonist. In the non-obstetric population, remifentanil has a rapid onset of peak effect (blood-brain equilibration time, 1.2-1.4 min), short duration of action independent of infusion duration (context-sensitive half-life, 3 min), and rapid clearance (40 ml/kg/min). These qualities introduce the potential for titratability during labor. In fact, the physiologic changes of pregnancy (e.g. increased cardiac output) are expected to further speed the onset, while the clearance rate is increased as well (Kan RE et al., “Intravenous remifentanil: placental transfer, maternal and neonatal effects,” Anesthesiology, 1467-74 (1998)). Remifentanil's unique pharmacokinetic profile is attributed to rapid metabolism by nonspecific esterases in blood and tissues.
Unfortunately, side effects of remifentanil are similar to those of other opioids (such as nausea, sedation, respiratory depression), the only difference being that with remifentanil, the side effects rapidly resolve with dose reduction or temporary discontinuation of the agent. Sometimes, to ensure adequate analgesia during a contraction, continuous infusion of remifentanil provided, which produces unacceptable levels of sedation between contractions. Attempts to administer remifentanil by PCA (patient-controlled analgesia) have been complicated by the delay in the onset of analgesia from (1) maternal sensation of a contraction, to (2) pressing the PCA button, to (3) bolus administration, to (4) clinical effect. Accordingly, some lead-time is needed to start the bolus such that the analgesia will be effective at the time of contraction. Unfortunately, there are no methods available to provide the lead-time necessary to initiate administration of the analgesia to peak with a contraction.
As noted herein, current forms of analgesia do not effectively address pain management during labor for those who cannot or choose not to receive a neuraxial block. Accordingly, a labor analgesia system is needed that can effectively manage pain during labor via analgesic administration that matches the timing and intensity of contraction-induced pain.